title: FAK-heterozygous mice display enhanced tumour angiogenesis.
abstract: Genetic ablation of endothelial focal adhesion kinase (FAK) can inhibit pathological angiogenesis, suggesting that loss of endothelial FAK is sufficient to reduce neovascularization. Here we show that reduced stromal FAK expression in FAK-heterozygous mice unexpectedly enhances both B16F0 and CMT19T tumour growth and angiogenesis. We further demonstrate that cell proliferation and microvessel sprouting, but not migration, are increased in serum-stimulated FAK-heterozygous endothelial cells. FAK-heterozygous endothelial cells display an imbalance in FAK phosphorylation at pY397 and pY861 without changes in Pyk2 or Erk1/2 activity. By contrast, serum-stimulated phosphorylation of Akt is enhanced in FAK-heterozygous endothelial cells and these cells are more sensitive to Akt inhibition. Additionally, low doses of a pharmacological FAK inhibitor, although too low to affect FAK autophosphorylation in vitro, can enhance angiogenesis ex vivo and tumour growth in vivo. Our results highlight a potential novel role for FAK as a nonlinear, dose-dependent regulator of angiogenesis where heterozygous levels of FAK enhance angiogenesis.
authors.affiliation: Vascular Adhesion Laboratory, BSRC Alexander Fleming, 34 Fleming Street, Vari, 166 72 Athens, Greece. kostourou@fleming.gr
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Kostourou
authors.forename: Tanguy
authors.initials: T
authors.lastname: Lechertier
authors.forename: Louise E
authors.initials: LE
authors.lastname: Reynolds
authors.forename: Delphine M
authors.initials: DM
authors.lastname: Lees
authors.forename: Marianne
authors.initials: M
authors.lastname: Baker
authors.forename: Dylan T
authors.initials: DT
authors.lastname: Jones
authors.forename: Bernardo
authors.initials: B
authors.lastname: Tavora
authors.forename: Antoine R
authors.initials: AR
authors.lastname: Ramjaun
authors.forename: Graeme M
authors.initials: GM
authors.lastname: Birdsey
authors.forename: Stephen D
authors.initials: SD
authors.lastname: Robinson
authors.forename: Maddy
authors.initials: M
authors.lastname: Parsons
authors.forename: Anna M
authors.initials: AM
authors.lastname: Randi
authors.forename: Ian R
authors.initials: IR
authors.lastname: Hart
authors.forename: Kairbaan
authors.initials: K
authors.lastname: Hodivala-Dilke
mesh_terms: D000818:Animals; D049109:Cell Proliferation; D002469:Cell Separation; D002470:Cell Survival; D042783:Endothelial Cells / Q000473:pathology; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D006579:Heterozygote; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D051379:Mice; D050505:Mutant Proteins / Q000378:metabolism; D009369:Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000473:pathology; D009389:Neovascularization, Pathologic / Q000201:enzymology* / Q000473:pathology; D051419:Paxillin / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction; D040521:Subcutaneous Tissue / Q000473:pathology; D016608:Talin / Q000378:metabolism; D047368:Tumor Burden; D016596:Vinculin / Q000378:metabolism
chemical_list: D050505:Mutant Proteins; D051419:Paxillin; D016608:Talin; D016596:Vinculin; D051417:Focal Adhesion Kinase 1; C496051:Ptk2 protein, mouse; D051057:Proto-Oncogene Proteins c-akt